Caruso Giuseppe, Privitera Anna, Saab Miriam Wissam, Musso Nicolò, Maugeri Salvatore, Fidilio Annamaria, Privitera Anna Provvidenza, Pittalà Alessandra, Jolivet Renaud Blaise, Lanzanò Luca, Lazzarino Giuseppe, Caraci Filippo, Amorini Angela Maria
Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy.
Unit of Neuropharmacology and Translational Neurosciences, Oasi Research Institute-IRCCS, 94018 Troina, Italy.
Biomedicines. 2023 Feb 6;11(2):474. doi: 10.3390/biomedicines11020474.
The activity of microglia is fundamental for the regulation of numerous physiological processes including brain development, synaptic plasticity, and neurogenesis, and its deviation from homeostasis can lead to pathological conditions, including numerous neurodegenerative disorders. Carnosine is a naturally occurring molecule with well-characterized antioxidant and anti-inflammatory activities, able to modulate the response and polarization of immune cells and ameliorate their cellular energy metabolism. The better understanding of microglia characteristics under basal physiological conditions, as well as the possible modulation of the mechanisms related to its response to environmental challenges and/or pro-inflammatory/pro-oxidant stimuli, are of utmost importance for the development of therapeutic strategies. In the present study, we assessed the activity of carnosine on human HMC3 microglial cells, first investigating the effects of increasing concentrations of carnosine on cell viability. When used at a concentration of 20 mM, carnosine led to a decrease of cell viability, paralleled by gene expression increase and decrease, respectively, of interleukin 6 and heme oxygenase 1. When using the maximal non-toxic concentration (10 mM), carnosine decreased nitric oxide bioavailability, with no changes in the intracellular levels of superoxide ion. The characterization of energy metabolism of HMC3 microglial cells under basal conditions, never reported before, demonstrated that it is mainly based on mitochondrial oxidative metabolism, paralleled by a high rate of biosynthetic reactions. The exposure of HMC3 cells to carnosine seems to ameliorate microglia energy state, as indicated by the increase in the adenosine triphosphate/adenosine diphosphate (ATP/ADP) ratio and energy charge potential. The improvement of cell energy metabolism mediated by 10 mM carnosine could represent a useful protective weapon in the case of human microglia undergoing stressing conditions.
小胶质细胞的活性对于调节包括大脑发育、突触可塑性和神经发生在内的众多生理过程至关重要，其体内平衡的偏离会导致包括多种神经退行性疾病在内的病理状况。肌肽是一种天然存在的分子，具有明确的抗氧化和抗炎活性，能够调节免疫细胞的反应和极化，并改善其细胞能量代谢。更好地了解基础生理条件下小胶质细胞的特征，以及对其应对环境挑战和/或促炎/促氧化刺激相关机制的可能调节，对于治疗策略的开发至关重要。在本研究中，我们评估了肌肽对人HMC3小胶质细胞的活性，首先研究了不同浓度肌肽对细胞活力的影响。当以20 mM的浓度使用时，肌肽导致细胞活力下降，同时白细胞介素6和血红素加氧酶1的基因表达分别增加和减少。当使用最大无毒浓度（10 mM）时，肌肽降低了一氧化氮的生物利用度，而超氧阴离子的细胞内水平没有变化。此前从未报道过基础条件下HMC3小胶质细胞能量代谢的特征，结果表明其主要基于线粒体氧化代谢，同时伴随着高比率的生物合成反应。HMC3细胞暴露于肌肽似乎改善了小胶质细胞的能量状态，这表现为三磷酸腺苷/二磷酸腺苷（ATP/ADP）比值和能量电荷电位的增加。10 mM肌肽介导的细胞能量代谢改善可能是人类小胶质细胞在应激条件下的一种有用的保护手段。
